5-177307831-T-C

Position:

• chr5-177307831-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031300.4(MXD3):​c.455A>G​(p.Asp152Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MXD3 NM_031300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

MXD3 (HGNC:14008): (MAX dimerization protein 3) This gene encodes a member of the Myc superfamily of basic helix-loop-helix leucine zipper transcriptional regulators. The encoded protein forms a heterodimer with the cofactor MAX which binds specific E-box DNA motifs in the promoters of target genes and regulates their transcription. Disruption of the MAX-MXD3 complex is associated with uncontrolled cell proliferation and tumorigenesis. Transcript variants of this gene encoding different isoforms have been described.[provided by RefSeq, Dec 2008]

MXD3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31806138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MXD3	NM_031300.4	c.455A>G	p.Asp152Gly	missense_variant	5/6	ENST00000439742.7	NP_112590.1
MXD3	NM_001394986.1	c.455A>G	p.Asp152Gly	missense_variant	6/7		NP_001381915.1
MXD3	NM_001394987.1	c.425A>G	p.Asp142Gly	missense_variant	4/5		NP_001381916.1
MXD3	NM_001142935.2	c.455A>G	p.Asp152Gly	missense_variant	5/6		NP_001136407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MXD3	ENST00000439742.7	c.455A>G	p.Asp152Gly	missense_variant	5/6	1	NM_031300.4	ENSP00000401867.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459588 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.455A>G (p.D152G) alteration is located in exon 5 (coding exon 5) of the MXD3 gene. This alteration results from a A to G substitution at nucleotide position 455, causing the aspartic acid (D) at amino acid position 152 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0031	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	.;.;D;D;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;T;.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.8	M;M;M;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0070	D;T;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;.
Polyphen		0.020	B;.;B;B;.
Vest4		0.34
MutPred		0.26		Loss of stability (P = 0.0139);Loss of stability (P = 0.0139);Loss of stability (P = 0.0139);Loss of stability (P = 0.0139);.;
MVP		0.70
MPC		0.48
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.33
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1760926051; hg19: chr5-176734832;